The present invention relates to pyrazole compounds having HSD1 inhibitory activity. 11-Beta-hydroxysteroid dehydrogenase 1 (hereinafter, “11β-HSD1” or “HSD1”) catalyzes the interconversion of glucocorticoids (hereinafter, “GC”) between inert 11-keto forms (e.g. cortisone, 11-dehydrocorticosterone) and active 11β-hydroxy forms (e.g. cortisol, corticosterone, respectively). The enzyme, in vivo, prefers the reductase direction from 11-keto to 11β-hydroxy, in other words, the production of active GC.
11β-HSD1 is ubiquitously expressed, most notably in liver, lung, adipose tissue, vasculature, ovary and the central nervous system.
Recently, experimental results have suggested that the active form of GC produced through HSD1 as well as the enzyme itself is involved in several biological actions and diseases.
For example, the active GC is known to stimulate gluconeogenic enzymes and have effects at least in part in inducing hyperglycemia. In this situation, HSD1 can be a second source of GC production in addition to the adrenal glands.
As another example, continuous excess of the active GC in peripheral tissues, as observed in Cushing's syndrome, leads to insulin resistance, where HSD1 is considered to have an important role.
Also, in adipose tissue, active GC has been demonstrated to enhance the differentiation of preadipocytes into adipocytes. Mature adipocytes express HSD1 activity, which causes an increase in local concentration of the active form and further expansion of adipose tissue. Such an action of HSD1 should be critical in pathogenesis of obesity.
In addition, a local immunosuppressive effect of HSD1 in placental deciduas, and a relationship between the expression of the enzyme in adrenal cortex and the induction of adrenaline synthesis, have been suggested.
(The above are referred to in: Quinkler M, Oelkers W & Diederich S (2001) European Journal of Endocrinology Vol. 144, Pages 87-97; and Seckl J R & Walker B R (2001) Endocrinology Vol. 142, Pages 1371-1376.)
According to the above suggestions, it is expected that drugs having inhibitory effects against HSD1 would be useful for treating or preventing diabetes mellitus, obesity, metabolic syndrome in connection with any of such diseases, or any other diseases which occur by reason of the actions of HSD1.
Diabetes mellitus, the main feature of which disease is chronic hyperglycemia, introduces various metabolic abnormalities and shows symptoms of thirst, polydipsia, polyuria, and so on based on high glucose concentration. A continuing hyperglycemic state can also lead to diabetic complications such as retinopathy, nephropathy, neuropathy, and myocardial and/or cerebral infarction by reason of arteriosclerosis.
In treating diabetes, moderate suppression of hyperglycemia is critical in order that onset and progress of the complications would be repressed. For these purposes, dietetics, ergotherapy and pharmacotherapy are utilized in combination on a suitable basis and, amongst the pharmacotherapy, many approaches different in mechanisms of action have been attempted. In spite of those various existing methods, sufficient therapeutic effect has not ever been achieved.
Obesity is defined as a state of fatness coinciding with any disease that would be improved or not be progressed in case of weight decrease (e.g. diabetes, hyperlipidemia, hypertension) or with an excessive amount of fat in viscera. It is considered that, if such a state should continue, at least two of diabetes, hyperlipidemia, hypertension and related disorders would concur, followed by the onset of myocardial and/or cerebral infarction by reason of arteriosclerosis.
Major therapeutic methods in treating obesity are dietetics and ergotherapy, and pharmacotherapy is undertaken only if necessary, for example, because of difficulty in the first two alternatives. However, the existing drugs have several problems in adverse effects and usages, since most of them suppress feeding mainly via central action.
In consequence, development of any drug to treat diabetes and/or obesity with a novel mechanism of action has so far been required. Under these circumstances, it is expected that drugs having inhibitory effects against HSD1 would be useful as another alternative with separate mechanistic approach to treat diabetes mellitus, as well as a novel “adipose tissue-acting” class among other drugs against obesity.
As drugs in development to treat diabetes and/or obesity through inhibition of HSD1, for example, WO 03/104207 and WO 03/104208 disclose triazole compounds of the following general formula:
wherein:
A and B are taken separately or together;
when taken separately, A is halo, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted OC1-6alkyl or unsubstituted or substituted phenyl and B is —H, halo, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted OC1-6alkyl, unsubstituted or substituted —SC1-6alkyl, unsubstituted or substituted C2-6alkenyl, unsubstituted or substituted phenyl or unsubstituted or substituted naphthyl; and
when taken together, unsubstituted or substituted C1-4alkylene or unsubstituted or substituted C2-5alkanediyl;
each R1 is —H, —OH, halo, unsubstituted or substituted C1-10alkyl, unsubstituted or substituted C1-6alkoxy or unsubstituted or substituted C6-10aryl, or two R1 taken together are a fused C5-6alkyl (either unsubstituted or substituted) or unsubstituted or substituted aryl ring;
R2 and R3 are taken separately or together;
when taken together, (a) a C3-8 alkanediyl forming a fused 5-10 membered non-aromatic ring (optionally interrupted with 1-2 double bonds, either unsubstituted or substituted) or (b) a fused 6-10 membered aromatic monocyclic (either unsubstituted or substituted) or bicyclic group (either unsubstituted or substituted);
when taken separately, R2 is C1-14 alkyl (either unsubstituted or substituted), unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl, either unsubstituted or substituted C2-10 alkenyl, —CH2CO2H, —CH2CO2C1-6alkyl, —CH2C(O)NHRa, —NHRa or N(Ra)2 and R3 is unsubstituted or substituted C1-4alkyl, unsubstituted or substituted C2-10alkenyl, unsubstituted or substituted SC1-6alkyl, unsubstituted or substituted C6-10aryl, unsubstituted or substituted heterocyclyl or unsubstituted or substituted heteroaryl;
Ra is unsubstituted or substituted C1-3 alkyl, unsubstituted or substituted OC1-3 alkyl, unsubstituted or substituted C6-10 ArC1-6alkylene or unsubstituted or substituted phenyl;
However, the description provided in the noted applications does not disclose or suggest any of the compounds having the structure of the present invention.
The compounds of the present invention improve physicochemical (stability, etc.) and biological (activity to inhibit HSD1, specificity, bioavailability, metabolism, etc.) profiles, as a result of the selection of structural characteristics as disclosed herein.